Our long range objective is to obtain a better understanding of the regulatory processes that control carbohydrate and fat metabolism during exercise, and to apply this information to the prevention and treatment of non-insulin-dependent (adult onset)diabetes mellitus (NIDDM). Muscle contraction is associated with activation of glucose transport. The increase in muscle permeability to glucose can persist for a long time after cessation of exercise, and may be related to muscle glycogen depletion. It seems likely that if it were better understood, this "insulin-like" effect of exercise could play a major role in the treatment of NIDDM and in prevention of the deterioration in glucose tolerance and insulin sensitivity with aging. Major objectives of this research are to elucidate the mechanisms responsible for a) inducing the "insulin-like" effect of exercise on glucose uptake, b) the reversal of the increase in glucose transport after exercise is stopped, and c) the regulation of glycogen metabolism in muscle. The specific aims of the research outlined in this proposal are to answer the following questions: a) Is a Ca++ activated protease involved in the process that leads to the increase in muscle cell membrane permeability to glucose induced by stimulation of contraction? b) Does stimulation of muscle contraction result in translocation of glucose transporters from an intracellular site into the sarcolemma? c) Is it glucose transport per se, or glycogen synthesis, that is responsible for speeding reversal of the increase in permeability to glucose induced by stimulation of muscle contraction? d) Is a permissive action of insulin necessary for the activation of glusose transport by stimulation of muscle contraction? e) Is the effect of stimulation of muscle contraction on glucose transport mediated by bradykinin and/or prostaglandins? f) Why does phosphorylase activation reverse despite continued contractile activity? g) Do changes in intracellular PH paly a major role in the regulation of glycogenolysis in muscle during contractile activity? h) How do fatty acids bring about a slowing of glycogenolysis in contracting skeletal muscle? This research will be performed on isolated frog sartorius and rat epitrochlearis muscles, and in muscles of the perfused rat hindquarter preparation. The effects of contractile activity will be studied in muscles stimulated in situ and in vitro, as well as in intact rats exercised by means of treadmill running.